Abstract We propose an ultrasensitive rapid diagnostic test (RDT) to detect exposure to pulmonary flukes of the genus Paragonimus. Paragonimiasis affects an estimated 21 mi l l ion people and remains amongst the most neglected of all neglected tropical diseases (NTDs). This trematode is acquired upon ingestion of raw or undercooked freshwater crustaceans and migrates to the lungs where it forms cysts. Treatment is straightforward (praziquantel) but diagnosis is not. The classical method? detection of Paragonimus eggs in sputum or stool ? requires rarely available microscopy expertise, is slow throughput, and is limited to egg-producing adult flukes. With an effective drug at hand but no convenient diagnostic, a highly sensitive RDT is the missing piece to enable efficient clinical management of paragonimiasis. A paragonimiasis RDT is all the more needed when considering that many paragonimiasis symptoms resemble those of TB or lung cancer, including hemoptysis (blood in sputum), persistent cough, weight loss, and cysts in CT scans. Misdiagnosis is common and patients are incorrectly put on ineffective antibiotic regimens or toxic cancer chemotherapy, with serious consequences. This project combines two innovations: (a) the re ce nt di scovery of novel paragonimiasis bi omarkers by re searchers at Washi ngton Uni versi ty, who identified a list of 25 immunoreactive Paragonimus proteins. The two most promising antigens are myoglobin 1 and cysteine protease 6 (CP-6). On the basis of Western blots obtained with a small set of sera, antibodies to myoglobin 1 (total IgG) and CP-6 (IgG4 subtype) detect paragonimiasis with 100% sensitivity and 100% specificity, when using other trematode and nematode infections as comparators. (b) we have developed goldnanoshells, a novel plasmonic nanoparticle designed to increase the analytical sensitivity of RDTs, and applied them to over 20 different analytes. We have expertise with detecting IgG and IgG4 responses through our work on other helminth proteins (loa loa SXP-1 (loiasis), Wuchereria bancrofti Wb123 (lymphatic filariasis), and Onchocerca volvulus Ov16 (river blindness)). The human benefit of our RDT will be significant: (a) this will be the first commercial assay for paragonimiasis, (b) the RDT will further assist the differential diagnosis of tuberculosis, lung cancer, and other pulmonary diseases, (c) while high prevalence areas in Asia stand to benefit most from a new test, the assay would also be useful in the USA, despite low infection rates, as witnessed by the CDC?s interest in this project.